Figure 5.

Selecting regions for targeted fine-physics sampling from low-accuracy B3LYP/MM free-energy surfaces computed from sampling with PM6/MM reference potential for the benchmark enzymatic reaction. These surfaces are used for detecting reactants and the transition state (shown by shaded gray areas). The first surface (shown in green) is computed by reweighting the reaction coordinate distribution from PM6/MM sampling using the umbrella sampling method. Another low-accuracy surface (shown in black) is calculated by adding the linear expansion of the free-energy perturbation to the PM6/MM high-accuracy PMF.